Development of humoral and cellular immunity against self-cellular proteins in cancer patients is a phenomenal observation. The ability of immune system to sense the presence of the disease and to fight of the disease by generating autoantibodies against tumor antigens makes it a natural biosensor. Several screening technologies have been employed for the identification of tumor-specific antibodies in cancer patients. We have developed a multidimensional approach for the identification of diagnostic antigens that utilizes a combination of high-throughput antigen cloning and protein microarray-based serological detection of complex panels of antigens by exploiting the serum autoantibody repertoire directed toward tumor-associated antigens in cancer patients. Furthermore, validation of these antigens by different bioinformatics and biological approaches will reveal the diagnostic/prognostic utility of these antigens for personalized immunotherapy.